It is generally accepted that tumors evolve from a neoplastic accumulation of clonal cell populations. One uniform marker of clonality that appears to be acceptable and reproducible is the cellular pattern of X-chromosome inactivation. Knowledge of tissue clonality could very well make the difference between a diagnosis of benign disease, such as hyperplasia, and neoplastic disease, including malignancy. In instances of multifocal neoplastic disease, the pattern of X-chromosome inactivation could either support or rule out the possibility that lesions are derived from one another by metastatic spread. A study of tissue clonality could be of significant importance in determining patient prognosis and patient therapy. Thus, we propose to use X-chromosome inactivation studies in neoplastic and potentially neoplastic lesions of the oral cavity in women: 1) To confirm in a population of females that squamous cell carcinoma is composed of a clonal cell population. 2) To determine if some cases of precancerous proliferative verrucous leukoplakia (PVL) and verrucous hyperplasia (VH) are composed of clonal cell populations, and identify whether cases of PVL and VH which are clonal in composition are associated with an increased probability for the concurrent or subsequent development of invasive squamous cell carcinoma. Each of these aims will be tested by X-chromosome inactivation studies. To test our two hypotheses this investigation will utilize methylation sensitive restriction endonuclease (HpaII) treatment of DNA from archival, formalin-fixed tissue sections, followed by polymerase chain reaction (PCR) amplification of a portion of the human androgen-receptor gene (HUMARA) which contains polymorphic short tandem repeats (STR), which demonstrate heterozygosity in over 90% of cases. The amplified products will be analyzed by high resolution polyacrylamide gel electrophoresis and autoradiography. This approach should permit the analysis of the clonal composition of tissues from the great majority of female patient cases.